Met and Ron are two related receptor-tyrosine kinases that have been implicated in tumor growth and metastasis. Although the function of Met in cancer has been studied for more than twenty years, culminating in development of targeted therapies now in clinical trials, Ron has more recently emerged as a major player in cancer, where its expression usually correlates with more aggressive disease and poor outcomes. Our work has revealed that an alternatively transcribed, N-terminally truncated form of Ron, called 'short-form' or sfRon, is the major active Ron isoform in breast tumors from patients, and that it plays a significant role in the aggressiveness of tumors. sfRon expression is sufficient to convert slow growing, non-metastatic tumors into fast growing tumors that spontaneously metastasized from the mammary gland to liver and bones. Mechanistic studies revealed an interaction between sfRon and PI3K that was required for sfRon function. Blocking the ability of sfRon to interact with PI3K thoroughly abrogated the ability of sfRon to confer aggressive tumor behavior and completely blocked metastasis. In contrast, full length Ron appears to promote metastasis through activation of multiple signaling pathways. We hypothesize that deregulated production of sfRon protein in breast tumors promotes metastasis through selective activation of PI3K signaling, a function that is distinct from Ron activity. Furthermore, we hypothesize that inhibition of Ron and sfRon kinase activity will be a valid approach to reduce or block tumor progression and/or metastasis. We have devised three specific aims to test our hypothesis. First, we will determine if sfRon mRNA or protein is selectively stabilized in tumors by elucidating how sfRon is regulated at the post-transcriptional level, and whether ubiquitylation of sfRon plays a role in its function. Second, we will determine if Ron and sfRon promote metastasis through different pathways, by examining the signaling partners of each protein in breast cancer cells and whether Ron and sfRon interfere with the others' signaling. Third, we will determine whether Ron and/or PI3K inhibitors prevent tumor growth/metastasis by testing new compounds in both cell line xenograft models and in our new patient-derived tumorgraft models. PUBLIC HEALTH RELEVANCE: sfRon is a newly discovered contributor to tumor progression and metastasis. Our experiments to test new inhibitors of the Ron pathway will impact translational cancer research by providing pre-clinical data on a new target in highly innovative patient-derived tumor graft models of breast cancer. Our proposal to determine the mechanisms by which sfRon promotes tumor aggressiveness will also impact basic cancer research by uncovering a new understanding for the processes involved in tumor progression.